title: Baseline anti-NS4a antibodies in combination with on-treatment quantitative HCV-RNA reliably identifies nonresponders to pegylated interferon-ribavirin combination therapy after 4 weeks of treatment.
abstract: BACKGROUND
  Early detection of nonresponders to hepatitis C therapy limits unnecessary exposure to treatment and its side-effects. A recent algorithm combining baseline anti-NS4a antibodies and on-treatment quantitative PCR identified nonresponders to a combination of interferon and ribavirin after 1 week of treatment.
  
  
  OBJECTIVE
  To validate a stopping rule based on baseline anti-NS4a antibody levels and early on-treatment virological response in treatment-naive genotype 1 chronic hepatitis C patients treated with the current standard pegylated interferon and ribavirin combination therapy.
  
  
  METHODS
  Eighty-nine genotype 1 patients from the Dynamically Individualized Treatment of hepatitis C Infection and Correlates of Viral/Host dynamics Study treated for 48 weeks with standard 180 μg pegylated interferon (PEG-IFN)-α-2a (weekly) and ribavirin 1000-1200 mg (daily) were analysed. Baseline anti-NS4a antibody enzyme-linked immunosorbent assay (NS4a AA 1687-1718) was performed on pretreatment serum. Hepatitis C virus-RNA was assessed at days 0, 1, 4, 7, 8, 15, 22, 29, weeks 6, 7, 8, 10, 12 and 6 weekly thereafter until end of treatment. Multiple regression logistic analysis was performed.
  
  
  RESULTS
  Overall 54 of 89 (61%) patients achieved sustained virological response. A baseline anti-NS4a antibody titre less than 1/1250 correlated with absence of favourable initial viral decline according to variable response types (P = 0.015). The optimal algorithm was developed using the combination of the absence of anti-NS4a Ab (<1/1250) at baseline and the presence of a viral load ≥ 100.000 IU/ml at week 4. This algorithm has a specificity of 43% and negative predictive value of 100% to detect nonresponse to standard PEG-IFN-α-2a and ribavirin therapy at fourth week of therapy (intention-to-treat analysis).
  
  
  CONCLUSIONS
  The decision to stop the therapy in genotype 1 chronic hepatitis C patients treated with PEG-IFN-α-2a and ribavirin can be confidently made after 4 weeks of treatment based on the absence of baseline anti-NS4a Ab and a week-4 hepatitis C virus-RNA above 100.000 IU/ml.
authors.affiliation: Department of Gastroenterology and Hepatology, AZ St Jan AV, Bruges, Belgium. Hans.Orlent@azbrugge.be
authors.forename: Hans
authors.initials: H
authors.lastname: Orlent
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desombere
authors.forename: Bettina
authors.initials: B
authors.lastname: Hansen
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.forename: Bart
authors.initials: B
authors.lastname: Haagmans
authors.forename: Robert J
authors.initials: RJ
authors.lastname: De Knegt
authors.forename: Solko W
authors.initials: SW
authors.lastname: Schalm
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000276:immunology*; D003661:Decision Support Techniques; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology*; D006526:Hepatitis C / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018937:Hepatitis C Antibodies / Q000097:blood*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000097:blood*; D011994:Recombinant Proteins; D015203:Reproducibility of Results; D012254:Ribavirin / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D013997:Time Factors; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D002352:Carrier Proteins; D018937:Hepatitis C Antibodies; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; C455041:NS4A cofactor peptide, Hepatitis C virus; D012367:RNA, Viral; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a